Post-Acute COVID-19 Syndrome
Conditions
Brief summary
REVERSE-LC is a phase 3 trial of baricitinib versus placebo in adults with neurocognitive impairment (a form of Alzheimer's Disease and Related Dementias or ADRD) or cardiopulmonary symptoms due to Long COVID.
Detailed description
This is a multi-site randomized, placebo-controlled, double-blind, parallel-design REVERSE-LC phase 3 study. Individuals meeting inclusion criteria will be randomized to one of two arms: the intervention arm of baricitinib 4 mg daily for 24 weeks (dose adjusted to 2 mg or 1 mg for baseline renal dysfunction) versus the placebo arm for 24 weeks. In addition to safety, a variety of clinical and biological outcome measures will be assessed.
Interventions
DRUGBaricitinib 4 MG
Nonproprietary name: Baricitinib
DRUGPlacebo
Placebo
Sponsors
Emory University
University of California, San Francisco
University of Minnesota
Vanderbilt University
Yale University
Vanderbilt University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The block size and treatment allocation will only be known to the biostatistician creating the randomization list and will not be shared with trial investigators or any other study personnel. This list will be directly uploaded into REDCap's randomization module. This maintains the concealment of future allocations and has been used successfully for several of our large RCTs. The details of the randomization procedure including details regarding stratification and block sizes will fully be reported in the trial publication to enable readers to assess the risk of bias. Randomization assignments will be accessible 24 hours a day, 7 days a week to the study coordinators and staff
Intervention model description
Randomized, placebo-controlled, double-blind, parallel-design superiority design
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 1. Obtain a signed and dated informed consent form from participant 2. State their willingness to comply with all study procedures and availability for the duration of the study 3. Male or female, aged ≥18 years old 4. Meet the following criteria for Post-COVID Condition or Long COVID: 1. 6-months prior, documented SARS-CoV-2 infection 2. Cognitive impairment as defined by having at least 20% positive (worse or much worse) items on the ECOG assessment 3. Neurocognitive symptoms must have been present for at least 60 days prior to screening. Symptoms that wax and wane must have been initially present at least 60 days prior to screening. 5. Ability to take oral medication and be willing to adhere to the baricitinib regimen 6. Females of childbearing potential must agree to either abstinence or use at least one acceptable method of contraception from the time of screening though at least 28 days after the end of the study intervention period. Note: Acceptable methods include barrier contraceptives (condoms or diaphragm) with spermicide, intrauterine devices (IUDs), hormonal contraceptives, oral contraceptive pills, and surgical sterilization.
Exclusion criteria
An individual who meets any of the following criteria will be excluded from participation in this study: 1. Pre-existing cognitive impairment not exacerbated by acute COVID as determined by study physicians after thorough review of participant's history and medical records 2. Current use of baricitinib or other disease-modifying antirheumatic drug (DMARDs) 3. Known allergic reactions to components of the baricitinib 4. Have ever been randomized in this study or any other study investigating baricitinib 5. Positive SARS-CoV-2 PCR or rapid Antigen test in the past 14 days 6. Pregnancy or breastfeeding 7. Any history of venous thromboembolism ever 8. History of malignancy or lymphoproliferative disorder 9. Renal dysfunction with estimated glomerular filtration rate of \< 30 mL/min/1.73m2 10. Absolute Neutrophil Count (ANC) \<1200 cells/mm3 11. History or evidence of severe or end-stage liver disease (e.g. bilirubin ≥1.5x or AST/ALT \>2x normal). 12. Positive Hepatitis B surface antibody, antigen or core antibody, or Positive Hepatitis C RNR or antigen 13. Positive HIV 4th generation (antibody/antigen) ELISA test 14. Have had symptomatic herpes zoster infection within 3 months prior to study entry or have a history of disseminated/complicated herpes zoster or herpes simplex infection 15. History of latent (diagnosed with Quantiferon testing) or active tuberculosis 16. History of a current or recent (\< 30 days from screening) clinically significant viral, bacterial, fungal, or parasitic infection 17. History of chronic alcohol abuse, Intravenous (IV) drug abuse, or other illicit drug abuse within the 2 years prior to study entry 18. Are immunocompromised and, in the opinion of the investigator, are at an unacceptable risk for participating in the study 19. Treatment with another investigational drug or other intervention \< 30 days of study enrollment 20. Are unable or unwilling to make themselves available for the duration of the study and/or are unwilling to follow study restrictions/procedures 21. Severe cognitive, physical, or psychological disability that would prevent participation in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Enrollment | 6 months | 2 participants per month, on average, are randomized |
| Diversity in enrollment | 6 months | 40% of participants will be from individuals disproportionally affected by COVID (Black, Hispanic, Asian, American Indian) |
| Study drug prescribed | 9 months | 80% of participants received every prescribed dose of the study drug |
| Study withdrawals | 18 months | Less than 20% participants will be deemed lost to follow up |
| Adverse event reporting | 18 months | 100% of Serious Adverse Events reported to Data Safety Monitoring Board within 24 hours of study team awareness |
| Study dosing | 9 months | 100% adherence to study drug dose adjustments guidelines |
| Study completion | 18 months | 80% of participants adhere to all study procedures and requirements |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Post-Exertional Malaise | 9 months | Assess percentage changes of post-exertional malaise using De Paul Symptom Questionnaire - Post-Exertional Malaise (DSQ-PEM) in the baricitinib arm compared to the placebo arm from baseline to week 12 |
| Shortness of Breath | 9 months | Assess percentage changes of the effect of breathlessness on daily activities using the Modified Medical Research Council Dyspnea Scale (mMRC) in the baricitinib arm compared to the placebo arm from baseline to week 12 |
| Severe and Serious Adverse Events | 9 months | Compare the percentage of severe and serious adverse events between study arms from baseline to week 12. |
| Inflammation biomarkers | 9 months | Decreases in plasma biomarkers of inflammation in the baricitinib arm compared to placebo arm from baseline to week 12 |
| Viral Reservoirs | 9 months | Decreases in viral reservoirs for the baricitinib arm compared to placebo arm from baseline to week 12 |
| Symptom Burden | 9 months | Assess percentage changes of post COVID-19 symptom burden using the Symptom Burden Questionnaire for Long COVID (SBQ-LC) Circulation Subscale in the baricitinib arm compared to the placebo arm from baseline to week 12 |
| Premature study discontinuation | 9 months | Compare the rate of study drug/placebo premature discontinuation by study arm (tolerability) |
| Global Neuropsychological Function | 9 months | Assess percentage changes of global neuropsychological function as measured using the CNS Vital Signs Neurocognition Index cognitive battery between baricitinib and placebo study arm from baseline to week 12. |
| Cardiopulmonary testing | 9 months | Assess percentage changes of exercise capacity (peak VO2) using cardiopulmonary exercise testing (CPET) in the baricitinib arm compared to the placebo arm from baseline to week 12 |
| Everyday Cognition | 9 months | Assess percentage changes of cognitive impairment using Everyday Cognition (ECog) scale in the baricitinib arm compared to the placebo arm from baseline to week 12 |
| Functional Status | 9 months | Assess percentage changes of functional status measures in the baricitinib arm compared to the placebo arm from baseline to week 12 |
| Quality of Life Measures | 9 months | Assess percentage changes of quality of life measures in the baricitinib arm compared to the placebo arm from baseline to week 12 |
Countries
United States
Outcome results
None listed